Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death

EBioMedicine. 2016 Sep;11:253-261. doi: 10.1016/j.ebiom.2016.08.020. Epub 2016 Aug 13.

Abstract

Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca2+ release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca2+ release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca2+ release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca2+ release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE.

Keywords: Calcium; Neurodegeneration; Nitric oxide; Ryanodine receptor; Seizures.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channel Agonists / pharmacology
  • Cell Death / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Epilepsy / metabolism*
  • Epilepsy / pathology
  • Humans
  • Kainic Acid / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide / pharmacology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*

Substances

  • Calcium Channel Agonists
  • Ryanodine Receptor Calcium Release Channel
  • Nitric Oxide
  • Kainic Acid
  • Calcium